Identification of QTL that Interact with Myostatin Genotype in C57BL/6 x M16i Mice
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Myostatin, or GDF8, regulates skeletal muscle growth and adipose development in mice, cattle and humans. Individuals with non-functional myostatin mutation exhibit excessive muscle growth, decrease fat mass and huge body size. Previous studies indicated that epistatic interaction might play an important role in the myostatin pathway. However, only several loci that have a significant interaction with myostatin genotype have been identified in mice and cattle.
In this dissertation work, we performed a QTL mapping study in F2 mice derived from a C57BL/6 myostatin-null mouse line and the M16i obese mouse line. A large number of traits were collected, which included 14 body weight traits, 10 obesity-related traits, 11 body composition traits, three bone strength traits and eight eQTL traits from 1000 F2. A total of 242 SNPs across the genome were genotyped for each mouse by Sequenom. A linkage map was constructed using the marker and pedigree information. Interval mapping was applied to identify main effect QTL for these traits. In addition, additive, dominance and imprinting effects were evaluated for each QTL position. The corresponding variation accounted for by the QTL was computed as well. Comparing different QTL models with QTL effect, myostatin genotype effect and the interaction between QTL and myostatin genotype, comparison-wise P-values were obtained to identify possible epistatic loci that interact with myostatin genotype. A similar approach was utilized to search for loci that have significant interactions with sex or reciprocal cross.
We identified a total of 115 main effect QTL. Among them, 10 QTL exhibited a significant imprinting pattern. In addition, 38 QTL were detected for their interaction with myostatin genotype with comparison-wise P-values less than 0.05. Most of them were associated with body weight and obesity-related traits. A total of 44 sex-specific and 41 cross-specific loci were discovered as well. Some of these QTL regions overlapped and this indicates possible pleiotropic effects. These QTL explained a large amount of phenotypic variation.
To the best of our knowledge, a large proportion of these QTL have not been identified in previous studies. This work is the first research to investigate epistatic interaction between genetic variation and myostatin genotype for bone strength and organ weight traits. The outcome of this work elucidates that epistatic interacting patterns widely exist between genetic loci that regulate muscle mass and fat accumulation. Moreover, the results from this dissertation work provide a foundation for future fine mapping work.